Li Xiaofang, Sun Wenxuan, Xu Xiaolan, Jiang Qirong, Shi Yuheng, Zhang Huixi, Yu Weien, Shi Bisheng, Wan Simin, Liu Jiangxia, Song Wuhui, Zhang Jiming, Yuan Zhenghong, Li Jianhua
Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.
Nat Commun. 2025 May 17;16(1):4591. doi: 10.1038/s41467-025-59985-8.
Hepatitis B virus (HBV) exclusively infects hepatocytes and produces large amounts of subviral particles containing its surface antigen (HBsAg). T cell immunity is crucial for controlling and clearing HBV infection. However, the intercellular processes underlying HBsAg presentation to T cells are incompletely understood. Here, using preclinical mouse models, we show that, following HBsAg expression, the intrahepatic Batf3XCR1CCR7 conventional dendritic cell subset cDC1 presents HBsAg by MHC-I cross-dressing, driving CD8 T cell response. Meanwhile, upon HBsAg access to lymphoid tissues, B cells acquire HBsAg directly in the follicles of lymphoid tissues and initiate CD4 T cell responses sequentially in the follicular and interfollicular regions, guided by chemoattractant receptors CCR5 and EBI2, respectively. Finally, we identify ALCAM, LFA-1, and CD80 as key co-stimulatory signals essential for optimal T cell responses. Thus, these findings reveal the roadmap of non-canonical antigen presentation that drives T cell immunity against HBsAg, advancing novel therapeutic strategies for chronic HBV infection.
乙型肝炎病毒（HBV）仅感染肝细胞，并产生大量含有其表面抗原（HBsAg）的亚病毒颗粒。T细胞免疫对于控制和清除HBV感染至关重要。然而，HBsAg呈递给T细胞的细胞间过程尚未完全清楚。在这里，我们使用临床前小鼠模型表明，在HBsAg表达后，肝内Batf3 + XCR1 + CCR7传统树突状细胞亚群cDC1通过MHC-I交叉提呈来呈递HBsAg，从而驱动CD8 T细胞反应。同时，当HBsAg进入淋巴组织时，B细胞在淋巴组织的滤泡中直接获取HBsAg，并分别在趋化因子受体CCR5和EBI2的引导下，依次在滤泡和滤泡间区域启动CD4 T细胞反应。最后，我们确定ALCAM、LFA-1和CD80是最佳T细胞反应所必需的关键共刺激信号。因此，这些发现揭示了驱动针对HBsAg的T细胞免疫的非经典抗原呈递路线图，为慢性HBV感染推进了新的治疗策略。
